An enzymatic activation of formaldehyde for nucleotide methylation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 07 2021
27 07 2021
Historique:
received:
29
01
2021
accepted:
05
07
2021
entrez:
28
7
2021
pubmed:
29
7
2021
medline:
5
8
2021
Statut:
epublish
Résumé
Folate enzyme cofactors and their derivatives have the unique ability to provide a single carbon unit at different oxidation levels for the de novo synthesis of amino-acids, purines, or thymidylate, an essential DNA nucleotide. How these cofactors mediate methylene transfer is not fully settled yet, particularly with regard to how the methylene is transferred to the methylene acceptor. Here, we uncovered that the bacterial thymidylate synthase ThyX, which relies on both folate and flavin for activity, can also use a formaldehyde-shunt to directly synthesize thymidylate. Combining biochemical, spectroscopic and anaerobic crystallographic analyses, we showed that formaldehyde reacts with the reduced flavin coenzyme to form a carbinolamine intermediate used by ThyX for dUMP methylation. The crystallographic structure of this intermediate reveals how ThyX activates formaldehyde and uses it, with the assistance of active site residues, to methylate dUMP. Our results reveal that carbinolamine species promote methylene transfer and suggest that the use of a CH
Identifiants
pubmed: 34315871
doi: 10.1038/s41467-021-24756-8
pii: 10.1038/s41467-021-24756-8
pmc: PMC8316439
doi:
Substances chimiques
Flavins
0
Nucleotides
0
Formaldehyde
1HG84L3525
Thymidylate Synthase
EC 2.1.1.45
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4542Informations de copyright
© 2021. The Author(s).
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